elastin and Hypertension--Renovascular

Increased vascular matrix metalloproteinases (MMPs) levels play a role in late phases of hypertensive vascular remodeling. However, no previous study has examined the time course of MMPs in the various phases of two-kidney, one-clip hypertension (2K1C). We examined structural vascular changes, collagen and elastin content, vascular oxidative stress, and MMPs levels/activities during the development of 2K1C hypertension. Plasma angiotensin converting enzyme (ACE) activity was measured to assess renin-angiotensin system activation. Sham or 2K1C hypertensive rats were studied after 2, 4, 6, and 10weeks of hypertension. Systolic blood pressure (SBP) was monitored weekly. Morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin, orcein and picrosirius red sections. Aortic NADPH activity and superoxide production was evaluated. Aortic gelatinolytic activity was determined by in situ zymography, and MMP-2, MMP-14, and tissue inhibitor of MMPs (TIMP)-2 levels were determined by gelatin zymography, immunofluorescence and immunohistochemistry. 2K1C hypertension was associated with increased ACE activity, which decreased to normal after 10 weeks. We found increased aortic collagen and elastin content in the early phase of hypertension, which were associated with vascular hypertrophy, increased vascular MMP-2 and MMP-14 (but not TIMP-2) levels, and increased gelatinolytic activity, possibly as a result of increased vascular NADPH oxidase activity and oxidative stress. These results indicate that vascular remodeling of renovascular hypertension is an early process associated with early increases in MMPs activities, enhanced matrix deposition and oxidative stress. Using antioxidants or MMPs inhibitors in the early phase of hypertension may prevent the vascular alterations of hypertension.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Blood Pressure; Collagen; Elastin; Enzyme Activation; Fluorescent Antibody Technique; Hypertension, Renovascular; Immunohistochemistry; Male; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; NADPH Oxidases; Oxidative Stress; Protease Inhibitors; Rats; Rats, Wistar; Reactive Oxygen Species; Renal Artery; Time Factors; Tissue Inhibitor of Metalloproteinase-2

The aim was to assess the influence of the renin-angiotensin system on the geometrical and elastic properties of the aorta in conscious dogs, using a model of renovascular hypertension, and to examine the effects of inhibition of the system by the angiotensin converting enzyme inhibitor spirapril.. The aortic elastic behaviour in response to renovascular hypertension was studied in 15 conscious dogs instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. Renovascular hypertension was induced by surgical occlusion of one renal artery and stenosis of the other. One day after renal surgery, dogs were randomly assigned to two groups receiving for two months either the new angiotensin converting enzyme inhibitor spirapril (n = 8) or a placebo capsule (n = 7). The two groups of dogs were compared to a control group of normotensive dogs (n = 7). After two months of treatment the elastic properties of the aorta were studied by computation of the beat to beat pressure-diameter hysteresis loops obtained during transient increase of pressure induced by bolus doses of angiotensin. The aortic pressure-diameter (P-D) relationship, obtained over a wide range, was fitted by an exponential fit (P = alpha.e beta D), where beta is the stiffness index. A decomposition of the P-D curve according to a biphasic model of the parallel arrangement of elastin and collagen enabled two pressure-diameter elastic moduli to be obtained, one representing the resistance to stretch at low pressure levels (elastic fibres and smooth muscle), and the other representing the resistance to stretch at the highest pressures (collagen fibres).. The pressure-diameter curve of the placebo group was shifted to the left compared to the curves of the control and spirapril groups, showing that renovascular hypertension was associated with isobaric reduction of aortic diameter. The stiffness index beta was higher (p < 0.05) in the placebo group [0.605(SD 0.304) mm-1] than in either the control group [0.362(0.126) mm-1] or the spirapril group [0.348(0.083) mm-1], suggesting that renovascular hypertension was associated with aortic stiffening. The biphasic analysis showed that the collagen pressure-diameter elastic modulus was unaffected by spirapril, whereas the elastin pressure-diameter elastic modulus was significantly reduced by converting enzyme inhibitor with respect to the placebo (p < 0.05).. Chronic converting enzyme inhibition by spirapril prevents the isobaric aortic diameter reduction induced by renovascular hypertension in conscious dogs and decreases aortic stiffness, in particular by changing the elastic behaviour of the elastin fibres rather than of the collagen fibres.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Dogs; Elasticity; Elastin; Enalapril; Hemodynamics; Hypertension, Renovascular; Male

Incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries in two-kidney, one-clip hypertensive rats was greater than that in normotensive rats. Splanchnicotomy predominantly over the root of mesenteric arteries or intracranioventricular injection of 6-hydroxydopamine prevented the development of hypertension in 2K-1C rats concomitant with the reduction of incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries. The content of norepinephrine in the hypothalamus in 2K-1C rats was lower than that in normotensive control rats. These findings indicate that increased non-collagenous protein synthesis in mesenteric arteries or low level of hypothalamic norepinephrine has facilitative effects on the development of 2K-1C hypertension.

Topics: Animals; Aorta; Collagen; Elastin; Hypertension, Renovascular; Hypothalamus; Male; Mesenteric Arteries; Myocardium; Norepinephrine; Proline; Rats; Rats, Wistar; Sympathetic Nervous System; Tritium

Segments of carotid, femoral, saphenous, and left circumflex coronary arteries were obtained from control, renal hypertensive, and nephrectomized hypertensive dogs for in vitro study of mechanical properties. Hypertension was produced in two-kidney dogs by unilateral renal artery constriction. After 3 months, the compromised kidney was removed in half of the dogs. Mean arterial pressure was significantly elevated in the hypertensive dogs after 3 months (127 +/- 2 vs 94 +/- 1 mm Hg for controls) and partially returned toward normal 3 months after nephrectomy (105 +/- 2 mm Hg). Pressure-diameter relations were determined under conditions of maximum active and passive smooth muscle activation. Contiguous segments were used for the determination of water and connective tissue content. Hypertension was associated with increased passive arterial wall stiffness at most sites, with a partial return toward normal after nephrectomy. Maximum responses to smooth muscle activation (active stress and constriction response) were augmented in arteries from hypertensive dogs and partially returned toward normal in the nephrectomized hypertensive group. The elastin content of these arteries was unchanged, while collagen content was nonuniformly decreased in renal hypertensive dogs. Small decreases were found in the radius-wall thickness ratio of some arteries. No significant mechanical changes occurred in the saphenous artery. The largest hypertension-related changes were found in the coronary arteries, which also exhibited the smallest recovery toward normal properties after nephrectomy. Considerable regional variability of changes in arterial wall in renal hypertensive and nephrectomized hypertensive dogs was found. Incomplete resolution of the hypertension and arterial wall changes by nephrectomy was found in this animal model.

Topics: Animals; Arteries; Biomechanical Phenomena; Collagen; Connective Tissue; Dogs; Elastin; Female; Hypertension, Renovascular; Male; Nephrectomy; Stress, Mechanical

Using rats made hypertensive by aortic ligation or by the one kidney--one clip method, we searched the aorta for morphologic clues that could explain why hypertension aggravates atherosclerosis. Both atherosclerosis and hypertension are characterized by an increased migration of mononuclear cells into the aortic intima; we therefore quantitated this phenomenon and studied its time course. In the thoracic aorta of hypertensive rats intimal cells (emigrated mononuclear cells) increased up to 15 times 2 weeks after surgery and remained stationary thereafter. In both control and experimental rats, leukocyte emigration was heavier in the thoracic aorta than in the abdominal region. A two- to threefold increase in medial smooth muscle herniae into the intima (myointimal herniae) was also found at 8 weeks, indicating a smooth muscle cell dysfunction. Electron microscopic study of the intima showed that its thickening was due to blood-borne material and also to extracellular matrix synthesized by the endothelium. Heightened secretion reflects cell activation, a condition that (in the endothelium) leads also to leukocyte adhesion. These data suggest that, in renovascular hypertension, the aortic endothelium is in an activated state, possibly through a hormonal stimulus.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Basement Membrane; Cell Adhesion; Collagen; Elastin; Endoplasmic Reticulum; Endothelium; Extracellular Matrix; Hypertension, Renovascular; Male; Microscopy, Electron; Monocytes; Muscle, Smooth, Vascular; Rats

Vascular structural changes were studied during the development of two-kidney one-clip renal hypertension. The weight of the arteries and the concentration and total amount of ribonucleic acid, deoxyribonucleic acid, alkali-soluble proteins, collagen and elastin of the vascular wall were measured. Tritiated thymidine uptake was also determined 15 and 30 days after clipping. Hypertension developed in 58% of the animals while the rest remained normotensive. A significant increase in artery weight and in the total amount of nucleic acids and proteins was found in hypertensive rats. The uptake of 3H thymidine by the arteries of hypertensive rats was significantly increased 15 days after clipping. This increment showed a significant correlation with blood pressure levels. Present data seem to indicate that the increase in vessel wall dimensions observed is partly due to an increase in the number of smooth muscle cells during the acute phase; this alteration appears to be mainly due to the rise in blood pressure.

Topics: Animals; Blood Pressure; Cardiomegaly; Collagen; Disease Models, Animal; DNA; Elastin; Hyperplasia; Hypertension, Renal; Hypertension, Renovascular; Male; Muscle, Smooth, Vascular; Myocardium; Rats; Rats, Inbred Strains; RNA; Thymidine

Topics: Animals; Blood Pressure; Carotid Arteries; Collagen; Elasticity; Elastin; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Muscle, Smooth; Norepinephrine; Rats